Cyanide-induced neurotoxicity is accompanied by a marked rise in cytosolic free calcium which activates a series of biochemical events culminating in the signs, symptoms and lesions of cyanide poisoning. This study will determine the underlying mechanism of the cyanide-induced rise in cytosolic calcium and investigate the intraneuronal reactions triggered by the elevated calcium. Proposed experiments will correlate the rise in cytosolic calcium with membrane potentials and intracellular ions (H+ and Cl-) by employing new fluorometric probes and a neurosecretory cell line (PC12 cells). Additionally, the relationship of glutamate excitotoxic neurotransmitter system to cyanide neurotoxicity will be studied in PC12 cells and mouse brain slices. The importance of the entry of cyanide anion through chloride channels will also be evaluated in isolated cells. Finally the contribution of cyanide-induced lipid peroxidation to perturbation of cell membranes will be determined in biochemical and morphological studies. The proposed work will give a more clear understanding of the mechanism of toxicity of a xenobiotic in the CNS and will correlate the biochemical defects, the structural alterations and the functional changes which characterize cyanide intoxication.